Significance/Aims. Obesity is characterized by increased body fat and propensity to numerous obesity-related illnesses, including hypertension, type II diabetes, cardiovascular, pulmonary and gallbladder disease, as well as some forms of cancer. The molecular basis of obesity in women is unknown. Obesity results from a positive energy balance. An individual may become obese with a normal rate of energy expenditure when intake is excessive, or with a normal level of food intake if energy expenditure is low. A low energy expenditure could be due to a metabolic defect or to hormonal abnormalities that are inherited. A novel polymorphism (TGGTrp --> CGGArg; codon 64) in the b3-adrenergic receptor gene was recently detected in a number of ethnic populations. The b3-adrenergic receptor is thought to play an important role in the regulation of energy expenditure and lipolysis. Subjects who harbor the polymorphism, tend to have a lower resting metabolic rate, higher body mass index and earlier onset of type II diabetes. Little is known, however, regarding the possible metabolic role of the b3-adrenergic receptor polymorphism as a contributor to low levels of energy expenditure that lead to obesity in older women. Our overall hypothesis is that the inherited polymorphism in the b3-adrenergic receptor gene contributes to the genetic basis of obesity via low levels of energy expenditure and fat metabolism in older women. Approach. Moderately obese women (50-65 y) who are homozygous or heterozygous for the b3-adrenergic receptor polymorphism will be weight-reduced, metabolically stabilized and compared to weight-reduced controls. We hypothesize that use of a post-obese model will unmask differences in energy expenditure that would otherwise be obscured by the obese state. Total daily energy expenditure, resting metabolic rate, the thermic effect of a meal, free-living physical activity, and fat metabolism will be compared among genotypes after weight reduction. These studies will help define the metabolic consequences of the b33-adrenergic receptor gene polymorphism in the regulation of daily energy expenditure and fat metabolism in older women.